Measuring API Particle Size Distribution

Q. Is there a clever way to directly measure drug/API particle size distribution in a tablet blend/granulation, assuming API has very low aqueous solubility and the excipients are in a mixed (either water-soluble or insoluble) state?

Ann Newman, PhD

A. One method that I have used to directly estimate/measure the particle size of API particles in tablets, which would also work for blends and granulations, is mapping. By picking a peak unique to the API, a visual distribution of the API can be obtained. In order to get a particle size distribution, you would need to extend the analysis by counting the dimensions for a relevant number of particles. Many times a simple visual assessment is enough to easily see differences based on parameters such as starting material or processing.

Mapping can be performed using a variety of techniques including infrared (IR), Raman, energy dispersive x-ray (EDX), and even X-ray powder diffraction (XRPD). EDX analysis, performed in a scanning electron microscope (SEM), can be used for API molecules that contain elements amenable to EDX (usually above carbon in the periodic table). In my project, the API contained a chloride ion that was not present in any of the excipients. By mapping the presence of the chloride, the API particle size present in two tablets were directly compared and related to dissolution data to help explain a slower dissolution rate. For spectral mapping, an API peak is needed that does not overlap with the excipients in the formulation. The API peak is then used to map the presence of the API in the sample. A visual map is obtained that can be used to estimate the particle size of the API visually or an additional step of measuring the size of relevant areas can be performed. The limitation will be the magnification of the microscope used; smaller particles will require higher magnifications. Resolution of the technique will also play a role and can be controlled by the instrument source and the experimental parameters. Higher resolution will require smaller analysis steps and longer scan times. These factors will need to be considered when you set up your experiment to determine the amount of time and effort that is needed for the information you want to obtain.